Preparation of 7{60 -methyl steroids

ABSTRACT

WHEREIN R is alkyl of one to four carbon atoms and R&#39;&#39; is selected from the group consisting of hydrogen, acyl of an organic carboxylic acid of one to 18 carbon atoms and an organic ether radical, a novel process for preparing the corresponding Delta 4,9,11-gonatrienes and novel intermediates produced by the said processes.   A novel process for the preparation of 7 Alpha -methyl- Delta 4,9-gonadienes of the formula

United States Patent Boucourt et al.

[451 Oct. 10,1972

[s41 PREPARATION OF 7a-METHYL STEROIDS [72] Inventors: Robert Boucourt; Lucien Nedelec,

both of Clichy-sous-Bois; Jean- Claude Gasc, Bondy, all of France [73] Assignee: Roussel UCLAF, Paris, France [22] Filed: July 27, 1970 [21] Appl. No.: 58,668

[30] Foreign Application Priority Data July 28, 1969 France ..6925702 [52] US. Cl. ..260/397.45, 260/397 .5, 260/999 [51] Int. Cl ..C07c 169/22 [58] Field of Search ..lMachine Searched Steroids [56] References Cited UNITED STATES PATENTS 3,341,557 9/1967 Babcock et al ..260/397.3

Primary Examiner-Henry A. French Attorney-Hammond & Littell [57] ABSTRACT A novel process for the preparation of 7a-methyl-A-- gonadienes of the formula 6 Claims, No Drawings PREPARATION OF 7a-METIIYL STEROIDS OBJECTS OF THE INVENTION THE INVENTION The novel process of the invention for the preparation of 7a-methyl-Af -gonadienes of the formula wherein R is alkyl of one to four carbon atoms and R is selected from the group consisting of hydrogen, acyl of an organic carboxylic acid of one to 18 carbon atoms and an organic ether radical comprises reacting a 1313- R-N-gonene of the formula with an acylating agent or a mixture of acylating agents of an organic carboxylic acid of one to carbon atoms to obtain a A -gonadiene of the formula .AcO oAe compound of the formula v dehydrobrominating the latter with a lithium halide in the presence of a basic agent to obtain a A -gonadiene ofthe formula OAc - 1 V reacting the latter with anorganornetallic agent containing a methyl group and saponifying the incompletely cleaved esters with a base to obtain a compound of the formula reacting the latter with an esterifying agent to form the compound of the formula 0 R' no? -I-0Ao" wherein Ac is acyl of an organic carboxylic acid of one i to 18 carbon atoms, treating the latter witha dehydrating agent to obtain a mixture of dehydrated products and treating. the said mixture with a strong acid in a protic media to obtain a compound of formula I wherein R is acyl of an organic carboxylic acid of one to 18 carbon atoms which may be saponified to obtain the corresponding compound of formula I wherein R is hydrogen. The said product can then be reacted with an etherification agent or esterification agent, if desired.

In the compounds of formula I, R is preferably methyl, ethyl,propyl or butyl. Examples of suitable organic acids of one to 18 carbon atoms may be derived from an aliphatic, aromatic, cycloaliphatic or heterocyclic carboxylic acid.- Examples of suitable acids are alkanoic acids, such as formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, trimethyl acetic acid, caproic acid, B-trimethyl propionic acid, heptanoic acid, caprylic acid, pelargonic acid, capric acid, undecylic acid, lauric acid, myristic acid, palmitic acid and stearic acid; alkenoic acids, such as undecylenic acid and oleic acid, cycloalkyl carboxylic acids, such as cyclopentyl carboxylic acid, cyclopropyl carboxylic propionic acid; aryl carboxylic acids, such as benzoic acid and 2,4-dinitrobenzoic acid; phenoxy alkanoic acids, such as phenoxy acetic acid, p-chlorphenoxy acetic acid, 2,4-dichlorophenoxy acetic acid, 4-ter-butylphenoxy acetic acid, 3-phenoxy propionic acid and 4-phenoxy butyric acid; heterocyclic carboxylic acids, such as furane-Z-carboxylic acid, S-terbutylfurane-Z- carboxylic acid, 5-bromo-furane-2-carboxylic acid and cyclopentyl nicotinic acids; B-ketoalkanoic acids, such as acetylacetic acid, propionylacetic acid and butyrylacetic acid; amino acids, such'as diethylaminoacetic acid and aspartic acid.

' The ethers 'of -R@ are preferably aliphatic such as lower alkyl, i. 'e. methyl, ethyl, propyl, butyl alkenyl such as allyl ,aryl such as benzyl or 'heterocyclic such propionyloxy -A"-gonadiene-3-one, 7a-methyl-1-3fiethyl-l,7B-beniyloxy-A" -gonadiene-3-one, 7a-methyll3fi-propybA -gonadiene-l 7B-ol3-one, 7a-methyl-l 3 B-propyl-l7[3-acetoxy-N- -gonadiene-3-one and 7amethyl- 1 3 B-propyll 7BY-benzoyloxy-A" -gonadiene-3- one.

The acylation of the compound of formula II in the 3, l l and 17 positions with enolization of the 3-keto group is preferably effected witha mixture of the corresponding acid .anhydride and acid chloride in the presence of a tertiary base such as a mixture of acetic acid anhydride and acetyl chloride in a pyridine media.

The selective bromination in the 6-position is preferably effected with N-bromosuccinimide in a mixture of dimethyl'formamide and water, but other classical. brominating methods maybe used such as bromine in a mixture of acetic acid and collidine.

The lithium halide used for the dehydrohalogenation is preferably lithium bromide. and the basic agent is preferably lithium carbonate and the said step is preferably effected in dimethylformamide. Advantageously, the process is effected without separation of the bromoderivative and the yields are higher for this process than when the bromo derivative is isolated.

The organo metallic derivative is preferably a methyl magnesiumhalide such as methyl magnesium bromide and the operation is effected advantageously in the presence of a catalyst such ascuprous iodide, bromide or chloride or cuprous acetate. After treatment with the .organo magnesium derivative and isolation, the ester functions of the steroids in the 1 1- and l7-positions. are incompletelycleaved and the completion of thesaponification of the ester groups is effected with a a base such as potassium hydroxide in an organic solvent such as methanol. 7

The selective acylation in the 17,-position can be effected by. known methods, for example, with acetic acid in. the presence of perchloric acid. The dehydration agent is preferably N-bromoacetamide in the presence. of sulfur dioxide although phosphorus oxychloride or thionyl chloride in the presence of pyridine maybe used.

The .mixture of raw products resulting from the dehydration step contains 7a-methyl-l3/3-R-l7/3- acyloxy-A."-gonadiene-3-one and other dienic compounds characterized by their infrared and ultraviolet spectra andthe'double bonds are either conjugated [5(l09( ll or non-conjugated [4,9 or 4,1 l].

The strong acid for the treatment of the dehydration product is preferably selected from the group consisting of perchloric acid, sulfuric acid, p-toluene sulfonic acid and a cationic sulfonic acid exchange resin and the protic media is acetic acid ora lower aliphatic alcohol. This treatment leads mainly to a mixture of 7a-methyl- 1 3 B-R- l 7B-acyloxy-A -gonadiene-3-one methyl- 1 BB-R-l 7B-acyloxy-A*-gonadiene-3-one which can be separated by chromatography.

The saponification of the latter compound may be effected by. potassium hydroxide in a methanolic media,

for example, to form 7a-methyl-l 3B-R'-A" -gonadiene- 'l7B1ol-3-one which can be esterified'or etherified by classical methods. The esterification of l7-hydroxy could be effected witha convenient acid functional derivative such as the acid anhydride or acid chloride in the presence of a tertiary amine. The etherification can be effected with a hydrocarbonhalide' with analkali metal derivative of the 17 hydroxyl preferably with the 3-keto protected by a ketal.

, The process of the invention results in the preparation of novel intermediates of the formula gonadienes of formula l as well as the corresponding A -gonatrienes. v

The intermediates of formula Va can be transformed by the process, of copending, commonly assigned application Ser. No. 58,730 filed oneven date herewith with the action of a dehydration agent into thecorrespondmg which have very interesting anabolic and androgenic properties. Using, the process of copending, commonly assigned application Ser. No. 58,666 filed on even date herewith, the intermediates of formula .Va can be' transformed into the corresponding 7a-methyl-13B-R-1 7a- Z -l7B-OZ -A-" -gonatriene-3=one wherein Z, aliphatic hydrocarbon and Z is hydrogen or acyl of an organic carboxylic acid which compounds. have marked anabolic and androgenic properties.

Examples of compounds of formula Va are: 7a-methyl-l 3 B-ethyl-N-gonene-l l/SJ 7B-diol-3- one, 7 1 7a-methyll 3B-ethyl- 1 7B-acetoxy-N-gonene- 1 1B- ol-3-one, Y r I 7a-methyll 3B.-ethyll 7B-phenylacetoxy-N-gonenellB-ol-3-one, 7a-methyll 3/3-ethyll 7B-propionyloxy-N-gonene- 1 lB-ol-3-one, 7a-methyll 3B-propyl-A-gonene-l 113,1 7B-diol-3 one, 7a-methyll BB-pro'pyll 7fi-acetoxy-Av-gonene-l l [3- ol-3-oneand 7a-methyl-1 3B-propyl-l 7B-benzoyloxy-A-gonenel 1/3-ol-3-one.

ln a variation of the process, one can produce 701- methyl-Au" -gonatrienes of the formula and 701- 7a-methyll 3B-R- l 7B-OX-A '.-gonadiene-3-one wherein R and R have the above definitions by reacting 7oz-methyl-l3B-R-17B-acyloxy-A -gonene-l lB-ol- 1O 3-one of formula Vll with a dehydrating agent to form a mixture of dehydration products, reacting the latter with oxygen in the presence of a tertiary amine to obtain' a hydroperoxide product,reacting the latter with a reducing agent to obtain thecorresponding 7a-methyll 3fl-R-l 7B-acyloxy-A -gonadiene-l 1B-3-one, reacting the latter with a strong acid in the presence of a nucleophilic agent in an aprotic solvent to form 7amethyl-13B-R-17B-acyloxy-A -gonatriene-3-one which may be saponified to obtain the corresponding 1713-01 compound which may be esterified or etherifled by the usual methods.

The raw product resulting from the reaction with the dehydration agent is a mixture of diverse dienic compounds whose double bonds may be conjugated or nonconjugated.

The dehydration agent is preferably N-bromo acetamide in the presence of sulfur dioxide but phosphorus oxychloride or thionyl chloride in the presence of pyridine can also be used. The oxydation of the dehydration product is preferably effected in the presence of a tertiary amine such as pyridine or triethylamine in an organic solvent, such as alcohols, i.e., methanol or ethanol or dialkylamide such as dimethyl formamide.

The reduction of the hydroperoxide is preferably effected with trimethyl or triethyl phosphite and is effected in an organic solvent such as ethanol or other alcohols or with an alkali metal iodide such as potassium iodide.

The reduction of the hydroperoxide gives a mixture of 7a-methyl-l 3,8-R-l 7/3acyloxy-A -gonadiene-3-one and 7a-methyl-l 3/3-R- l 7,B-acyloxy-A -gonadiene-1 1 ,B-ol-3-one which can be separated by chromatography. The latter compound is treated with a mineral acid such as sulfuric acid or perchloric acid or an organic acid such as formic acid or p-toluene sulfonic acid or a Lewis acid such a boron trifluoride to obtain the corresponding 7a-methyl-13,8-R-l7fi-acyloxy-A gonatriene-3-one. The nucleophile agent is preferably an organic acid nitrile such as acetonitrile, malonic dinitrile or dichloroacetonitrile, etc., or an alkali metal cyanide such as potassium or sodium cyanide, and the aprotic solvent may be methylene chloride, chloroform, cyclohexane, benzene, ether or tetrahydrofuran.

The saponification of the 17,8-acyloxy group of the latter compound may be effected with potassium hydroxide in a methanolic media. The esterification or etherification may then be effected in known methods.

The 13fl-R-A -gonenes of formula 11 useful as the starting materials in the process of the invention are described in French Pat. No. 1,574,693. I

The 7a-methyl-1 3B-R-A -gonadienel 7,B-ol-3-ones of formula 1 and the 7a-methyl-l3B-R-A gonatriene-l7B-ol-3-ones of formula VIII possess 6 anabolic and androgenic properties making themuseful for treatment of protidic anabolic troubles, of astheni'a, thinness, osteoporosis, andropause, aging, retarding of consolidation of fractures, metabolic troubles from prolonged corticotherapy, adiposogenital syndrome functional menometrorrhagia, fibromas, endometriosis, and as a healing agent for the treatment of various ulcers.

1n the following examples, there are described several preferred embodiments to illustrate the invention. However, it should be understood that the invention is not intended to be limited to the specific embodiments.

EXAMPLE I PREPARATION OF 7a-methyl-l 3B-ethyl-17B- acetoxy-A -gonadiene-3-one Step A: 3 ,1 1,3,17,B-triacetoxy-13,B-ethyl-A -gonadiene I 25 gm of l3B-ethyl-A -gonene-l lB,17B-diol-3-on'e (described in French Pat. No. 1,574,693) were added under a nitrogen atmosphere to a mixture of 250 cc of acetic acid anhydride, 8.75 cc of acetyl chloride and 8.75 cc of pyridine and the mixture was refluxed for 5% hours. After cooling, the mixture was concentrated to dryness under reduced pressure and the residue was dissolved in cc of a boilingmixture of acetic acid and methanol 8-2). The solution was treated with carbon black, filtered hot and the filtrate was concentrated to 100 cc. After cooling, crystal-lization was started and the mixture was filtered to obtain 25.5 gm of 3,11,13,17B -tri acetoxy-l3B-ethyl-A -gonadiene melting at 181 C. Concentration of the mother liquors and crystallization from a mixture of acetic acidmethanol gave a second crop of 4.4 gm of the said product melting at C. U. V. Spectrum (ethanol):

Max. at 234-235 mu 1R Spectrum (CCl Absorption at 1757 and 1208 i (enolic acetate); at 1738 and 1239 "f (acetate in 11 and 17); at 1668 and 1635 (double bond).

As far as is known, this compound is not described in the literature. Step B: 6 -bromo-1 1B,17,B-diacetoxy-l 3/3-ethyl-A- gonene-3-one 133.4 gm of 3,1 1B,17B-triacetoxy-l3B-ethy1-A gonene were added under a nitrogen atmosphere to a mixture of 450 cc of dimethylformamide and 7 cc of distilledwater and after cooling to 0C, 62 gm of N- bromosuccinimide were added over an hour thereto to obtain a positive amide-iodide paper test to obtain a solution of 6f-bromo-l 1,8,1 7,8-diacetoxy-l 3B-ethyl-A gonene-3-one which was used without isolation for the next step. The compound could be isolated, if desired, by concentration of the reaction mixture, dilution with Water, extraction with an organic solvent and concentration to dryness. I

As far as is known, this compound is not described in the literature. Step C: l 13,17B-diacetoxy-l3,B-ethyl-N- -gonadie ne- 3-one 33.2 gm of lithium bromide and 66.4 gm of lithium carbonate were added to the solution of Step B and the reaction mixture was heated for 17 hours at 95 C with I. R. Spectrum (CCL):

agitation. After cooling, the reaction mixture was made acidic with acetic acid and was stirred. The precipitate formed was recovered by vacuum filtration and was dried to obtain 120 gm of raw 1 1B,17B-diacetoxy-.13flethyl- A: -gonadiene3-one which was from isopropyl ether gave a product melting at l23l2 4 C. U.V. Spectrum-(ethanol):

Max. at 28l-282u e=23,000

Absorptions at 1659 (conjugatedketone); at 1619 and 1585 (double bond) and at 1725 (non-enolic acetate). 1 1 As far as isknown, this compound is not described in the literature. 1 STEP D: 7oi-rnethyl l3B ethyl A-gonene-1 1,8, 173- diol-3-one 2.8 gm-of powdered cuprous chloride in 545 cc of -a 0.92 M solution-of methyl magnesium bromide were stirred for 15 minutesat room-temperature, the mixture wascooled try-10C. Then a solution of '44 gm of 1 I B, 17B-diacetoxy-13/3-ethyl-A gonadiene-3-one in 290 cc of tetrahydrofuran was progressively added and then .thetemperature was allowed to return to 20C.

1 Afterstirring for 20 minutes, the reaction mixture was added to a water-hydrochloric acid mixture and the aqueous phase .was then extracted. with methylene chloride. Themethylene chloride extracts were washed with water, wer'e dried and concentrated to dryness. The residue was dissolved under a nitrogen atmosphere in a mixture of 450 of methanol and'45 cc of a 48 Beaqueous potassium hydroxide solution and the mixture. was refluxed for 1 hour and then-cooledl The mixture was added to water and was then acidified to a pH of 3.5 with aqueous hydrochloric acid. The aqueous phasewas extracted with methylene chloride and the methylene chloride extract was washed with water, dried and concentrated to'dryness. The residue was dissolved in methylene chloride and the resulting solution was passed through an activated magnesium silicate column, was concentrated to dryness and the residue was crystallized from a mixture of methanol and isopropyl ether to obtain 13.9 gm of raw 7a-methyl-l3 fi-ethyl-N-gonene-l lB,l7B-diol-3-one melting at 246C which was used as .is for the next step. The melting point of the purified product from methanolwas 248C.

UV Spectrum (ethanol):

Max. at 244 mp. 6= 16,700

RMN Spectrum.(deuterochloroform):

Peaks at 4248.5 hz (hydrogens at 7-methyl); at 6l.5-69-hz (hydrogens at 13-ethyl); at 225 hz (hydrogen at 170:); at 252 hz (Ila-hydrogen); and at 352.5.hz (4-hydrogen).

- As far asis known, thiscompound is not described in the literature.

STEP 'E: 7a-methyll 3B-ethyll 7B-acetoxy-N-gonenel lB-ol-3-one 23.5 gm of 7a-methyl-13B-ethyl-A-gonene-113,173 -diol-3-one melting at 246 C were added to a mixture of590 cc of acetic. acid and 23.5 cc of an aqueous 53 Be perchloric acid: solution under a nitrogen atmosphere and the reaction mixture was stirred for 5 hours at room temperature. The mixture was then amorphous V which was used as is for the next step. Crystallization after crystallization chloride extracts were washed successively with water, a saturated aqueous sodium bicarbonatesolution, and

thenwater, were dried and concentrated to dryness;

The residue was purified by chromatography over silica with elution with an 8-2 mixture of chloroform-acetone.

and crystallization from isopropyl ether to obtain 19.4 gm of 7a-methyl-1'3B-ethyl-l 7B-acetoxy-N-gonene-l 1 B-ol-3-one melting at 186 C.

UV Spectrum (ethanol):

max. at 243 my. F 16,900 IR Spectrum (CCl 'Absorptions at 1658 B531 (ketone); at 1610 (double bond); at 17122. (acetoxy); at 3600 1 (hydroxyl).

As far as is known, this compound is not described in the literature. STEP F: 7a-methyll BB-ethyl- 1 7fl-acetoxy-A gonadiene-3-one I 23 gm of 7Bvmethyl-13B-ethyl-l 7I3-acetoxy-N-gonenel lB-ol-3-one were added under a nitrogenatmosphere to 287cc of pyridine and after the addition of 13.1 gm of N-bromo acetamide to the reaction mixture, it was stirred for 15 minutes atroom temperature. After cooling to 0 C, sulfur dioxide was bubbled through the reaction mixture until an amide-iodide paper test was negative and the reaction mixture was then poured into a water-ice mixture. The aqueous phase was extracted 7 with methylene chlorideand the organic phase was washed with an aqueous hydrochloric acidsolution and ether and after stirring,.the organic phase was decanted off.-The aqueous phase was extracted with ether and the-ether extracts were washed with water, dried andconcentrated to dryness. The residue was purified by chromatography over silica gel and elution with a 3-1 mixture of ethyl ether and petroleum ether (Bp 35- C) to obtain 8.85 gm of a fraction rich in the desired product. The 8.85 gm was purified by dissolution in methylene chloride and passing the solution through an alumina column. The. methylene chloridesolution was concentrated to dryness and the residue was empasted with a hot mixture of petroleum ether (Bp 35-70 C) and isopropyl ether (9-l) to obtain 4.3 gm of raw product melting at C. Crystallization from a mixture of isopropyl ether and petroleum ether (Bp 35 :7, 0 C) gave 3.18 grngflg methyl-l3B-ethyl-l7,8-

acetoxy -A -gonadiene-3-one rnelting at 112 C and having a specific rotation [04], =27l (c 0.43% in Peaks at 43-50 hz (hydrogens of 7-methyl); at 53-60-67 hz (hydrogens of 13-ethyl); at 123112 (methyl hydrogens of l7-acetoXy); at 283 hz (17ahydrogen); and at 341 hz (t-hydrogen).

This compound is identical to 7a-methyl-l3B-ethyll7B-acetoxy-A -gonadiene-3-one described in Belgian Pat. No. 690,368.

EXAMPLE [I PREPARATION OF 7a-methyll 3B-ethyl- 1 7B- acetoxy-A -gonatriene-3-one Step A: 25.6 gm of 7a-methyl-l3B-ethyl-17B-acetoxy- A -gonene-l lB-ol-3-one were dehydrated by the procedure of Step F of Example I to obtain 21.6 gm of a mixture of raw dehydrated products. The entire mixture of raw dehydrated product was dissolved in 540 cc of ethanol containing 1 percent of triethylamine and a current of oxygen was bubbled through the solution for 6 hours. The reaction mixture was concentrated to dryness under reduced pressure.

The dried residue was dissolved under a nitrogen atmosphere in 192 cc of ethanol and 17.4 cc of triethyl phosphite were added to the reaction mixture which was then refluxed for 2 hours. After cooling, excess reducing agent was destroyed by the addition of oxygenated water until a positive amido-iodide paper test was achieved. The mixture was diluted with water and extracted with methylene chloride. The methylene chloride extracts were concentrated to dryness and the residue was purified by chromatography over silica gel with elution with a 3-1 mixture of ethyl ether-petroleum ether (Bp 35 70C) to obtain 11.2 gm of 7amethyl-l 3}3ethy1-l7fi-acetoxy-A -gonadiene-1 lB-ol- 3-one melting at 155C (not distinct).

IR Spectrum (CCl Absorptions at 1600 (double bond); at 1658 (ketone); at 1710 (carbonyl of acetate); and at 3540 (hydroxyl).

UV Spectrum (ethanol):

max.at2l4-2l5mp, e=3,700 max. at 236 mp. e=3,500 max. at 299 my. e= 13,200

The raw product was used as is for the next step.

As far as is known, this compound is not described in the literature. Step B: 2.75 gm of raw 7az-methyl-l3B-ethyl-17B- acetoxy-A '-gonadiene-1 lfi-ol-3-one were added under a nitrogen atmosphere to a mixture of 55 cc of pure methylene chloride (except for methanol), 11.15 cc of acetonitrile and 2.23 cc of an aqueous 65 percent of perchloric acid and after stirring the mixture for 2 minutes at room temperature, it was poured rapidly into a water-ice mixture. The aqueous phase was extracted with methylene chloride and the organic extracts were washed with water, dried and concentrated to dryness. The residue was purified by chromatography over silica gel and elution with a 3-1 mixture of ethyl ether petroleum ether (Bp 35-70C) to obtain 1.4 gm of 7a-methyl-l3B-ethyl-l7B-acetoxy- A- -"-gonatriene-3-one melting at 153 C. The product after crystallization from isopropyl ether had a melting point of 154 C and specific rotations [02],, 3 0.75 percent in ethanol) and l9.5 (c 0.75 percent in chloroform).

U.V. Spectrum (ethanol):

10 max. at 237-238 In e=6,100 lnflex. towards 271 mu 6 3,700 Max. at 340-341 my. 'e=29,800

RMN Spectrum (deuterochloroform) Peaks at 42.5 49.5 hz (hydrogens of 7-methyl); at 51-58-65 hz (hydrogens of l3-ethyl) at 125.5 hz (hydrogens of methyl of l7-acet0Xy); at 286-293-302 hz (Ha-hydrogen); at 347 hz (4-hydrogen); and at 377-387-400 hz (hydrogens in 11- and l2-position).

As far as is known, this compound is not described in the literature.

Various modifications of the products and process of the invention may be made without departing from the spirit or scope thereof and it is to be understood that the invention is to be limited only asdefined in the appended clairns.

We claim:

1. A process for the preparation of 7a-methyl-A-- gonadienes of the formula wherein R is alkyl of one to four carbon atoms and R is selected from the group consisting of hydrogen, acyl of with an acylating agent of an organic carboxylic acid of l to 10 carbon atoms to obtain a A -gonadiene of the formula AcO wherein Ac is acyl of an organic carboxylic acid of one to 10 carbon atoms, selectively brominating the latter in the 6-position with a brominating agent selected from the group consisting of bromine and N-ibromosuccinimide to obtain a compound of the formula AcO- OAc dehydrobrominating the latter with a lithium halide in L the presence of a basic agent to obtain a Af -gonadiene of the formula reacting the latter with'an esterif ying agent to form the] compound of the formula I 1 wherein Aci is acyl of an organic carboxylic acid of one to 18 carbon atoms; treating the latter with a dehydrating agent selected from the group consisting of thionylchloride, N-bromoacetamide and phosphorus oxychloride and treating the'resulting product with a strong acid in a protic media to obtain the desired 7ozmethyleN- gonadiene. I

2. A process for the preparation of 7a'-meth l- A gonatrien'el7B-ol of the formula wherin R is alkyl of one to four carbon atoms compris ing reacting 7a-methyl-l 3B-R-l 7B- acyloxy-A-gonenel lB-ol-3-one of the formula I wherein Ac is acyl of an organic c'arboxylic acid of one 25 to l8'carbonatoms, with a dehydrating agent selected from the group consisting of thionylchloride, N-

bro oaceta id a d hos horus ox chl ride -to form v a m iitture oi defiy rationriioducts, rsactingthe latter with oxygenin the (presence of a tertiary amine to ob- 30 tain a hydroperoxide product, reacting the latter with a reducing agentto obtain the corresponding 7B-methyll 3 1841- l 7B-acyloxy-Ar-gonadienel lB-ol-3-one,

reacting the latter with a strongacid in the presence: of

a nucl'eophilic agent in an aprotic solventto form 7&-

3 5 methyl- 1 3fi -R- l7fi-acyloxy-A- '"-gonatriene-3 -one and saponifying the latter to obtain the corresponding 

2. A process for the preparation of 7 Alpha -methyl- Delta 4,9, 11-gonatriene-17 Beta -ol of the formula
 3. 3, 11 Beta , 17 Beta -triacetoxy-13 Beta -ethyl- Delta 3,5-gonadiene.
 4. 6 xi -bromo-11 Beta , 17 Beta -diacetoxy-13 Beta -ethyl-Delta 4-gonene-3-one.
 5. 7 Alpha -methyl-13 Beta -ethyl-17 Beta -acetoxy- Delta 4,9-gonadiene-11 Beta -ol-3-one.
 6. 7 Alpha -methyl-13 Beta -ethyl-17 Beta -acetoxy- Delta 4,9, 11-gonatriene-3-one. 